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. 2022 Jun 7;8:277. doi: 10.1038/s41420-022-01077-3

Fig. 7. Schematic representation of mTOR crosstalk in RUNX2 regulation.

Fig. 7

This figure summarizes, along with the findings from the current study, where, at physiological levels, activation of mTORC2 by PIP2 resulted in activation of AKT by phosphorylation at Ser473. pSer473AKT inhibits GSK3β by phosphorylation at Ser9. Inhibitory/inactive Ser-9GSK3β fails to interact with RUNX2, and thus RUNX2 is stabilized from its degradation. Active RUNX2 can enhance ECM calcification and promote osteogenesis of MSCs. Increasing levels of glucose and glutamine or insulin can hyperactivate mTORC1 which through active p-70S6k inhibits mTORC2. Inhibition of mTORC2 results in destabilization of RUNX2 through the loss of pSer473AKT, which leads to activation of GSK3β. Active GSK3β interacts with RUNX2 and primes it for ubiquitination. mTORC1 also activates lipogenesis and helps to increase adipogenesis. Metformin activates AMPK by phosphorylation at Thr172, which inhibits mTORC1 and rescues mTORC2 under high-glucose and/or high-glutamine conditions.